All multicellular organisms comprise material with tensile strength and rigidity, such as bone and collagen, to maintain shape and to facilitate mechanical movement. Additionally, however, such organisms also must comprise a component with intrinsic elasticity, a component that can stretch and then undergo elastic recoil when required. For warm-blooded animals, this elasticity component is an unusual fibrous protein, elastin. Although elastin is present in virtually all tissue in some animals, it comprises an appreciable percentage of all protein in only some tissues, such as the arteries, some ligaments and the lungs. The elastin content of the human lung is about 28%.
Elastin can be hydrolized or otherwise destroyed by a select group of enzymes classified as elastases. The elastases are derived from many tissues in man, including the pancreas, neutrophils, macrophages, monocytes, platelets, smooth muscle cells and fibroblasts. Although called elastases, these enzymes are not just elastin-specific, and have been shown to cleave other proteins.
The role of elastases in normal elastin metabolism is difficult to assess, but a role in protein turnover is assumed. Human neutrophil granulocytes are the source of the neutral protease, human leukocyte elastase (HLE). HLE is a protease capable of hydrolysing most connective tissue components. However, its most likely primary physiologic substrate is elastin. Since destruction of elastin and the concomitant loss of elastic recoil in the emphysematous lung have been well established, HLE has been postulated to be the primary destructive agent in the pathogenesis of emphysema. Increased proteolysis, especially elastolysis, may occur in the lung parenchyma as a result of an imbalance between HLE and its major inhibitor, alpha-1-protease inhibitor, either because of an increased release of the enzyme in the lung or because of an acquired or inherited deficiency of the protease inhibitor. Cigarette smoke, which has been shown to oxidatively inactivate alpha-1-protease inhibitor in vitro, is believed to cause a localized functional deficiency of the protease inhibitor in the lungs of smokers. This breakdown of the antiprotease shield in lungs is thought to be a primary factor in the pathogensis of centrilobular emphysema associated with cigarette smoking.
Recently, certain trifluoromethyl ketone substituted peptide derivatives have been published, which derivatives are stated to be inhibitors of HLE. EP Appln. No. 86300379.4 (Publication No. 0189305-Jul. 30, 1986).